ABSTRACT The goal of the Center for Integrative Research on Childhood Leukemia and the Environment (CIRCLE) is to identify the causes of childhood acute lymphoblastic leukemia (ALL) and to support prevention efforts by educating health practitioners, families, and public health organizations on risk factors for leukemia. During the last half century, the incidence of childhood ALL has steadily increased in children, with the highest rates reported in Latinos. This rapid increase strongly supports the role of environmental exposures in the etiology of childhood ALL, either alone or in combination with genetic and epigenetic factors. Existing biological and epidemiological studies suggest that childhood ALL is often initiated in utero and fetal exposure to carcinogenic chemicals may play a role in the etiology of the disease. Given these findings and novel laboratory methods developed during CIRCLE?s first cycle, the overarching theme for the next cycle is to identify additional in utero chemical risk factors for childhood ALL in an ethnically diverse population, and to understand how chemicals increase risk via immunological, genetic and epigenetic mechanisms. CIRCLE will integrate population-based and basic research by using archived maternal pregnancy blood specimens and neonatal blood spots from the California Department of Public Health, and will leverage resources from two ongoing studies - the California Childhood Leukemia Study and the California Mother-Child Birth Cohort. Integrated statistical analyses of the Projects will assess the interplay between in utero chemical exposures, immune status, genetics, and epigenetics in ALL etiology. Core A will provide oversight, coordination, and integration of Center activities, establish an External Advisory Committee, coordinate community engagement, collaborate with the Pediatric Health Specialist, and support the research career development of a new Career Development Investigator. Project 1 will evaluate the impact of in utero chemical exposures on the risk of childhood ALL, taking into account the role of maternal and neonatal immune status, as measured by immunomodulatory cytokines in maternal pregnancy sera and neonatal blood spots. Project 2 will characterize the totality of endogenous and exogenous chemical exposures in maternal and neonatal biospecimens to identify novel in utero risk factors for childhood ALL. New methods for profiling small molecules and protein adducts will be applied, and targeted analyses will be performed for small molecules previously found to be associated with ALL. Project 3 will determine the perturbation of DNA methylation by chemical, immune, and dietary factors, incorporating constitutive genetics, and will evaluate the role of these factors in integrated risk analyses of childhood ALL. Core C will support Projects 1, 2, 3 to elucidate causal mechanisms in a mouse model with a propensity to develop a mouse-analog of childhood ALL. The Community Outreach and Translation Core (Core B) will contribute to environmental health literacy in various audiences, including Latinos, and provide a scientific basis for developing prevention programs for ALL in children.